scholarly journals Phenotype: Genotype Relationships in Growth Hormone Insensitivity Syndrome1

1997 ◽  
Vol 82 (11) ◽  
pp. 3529-3535 ◽  
Author(s):  
Katie A. Woods ◽  
Florence Dastot ◽  
Michael A. Preece ◽  
Adrian J. L. Clark ◽  
Marie-Catherine Postel-Vinay ◽  
...  
Keyword(s):  
Binding Protein ◽  
Receptor Gene ◽  
Gene Mutations ◽  
Compound Heterozygous ◽  
Gh Receptor ◽  
Ghr Gene ◽  
Wide Range ◽  
Growth Hormone Insensitivity ◽  
Igf Binding ◽  
Igfbp 3

GH insensitivity syndrome (GHIS) is associated with many different mutations of the GH receptor (GHR) gene. We examined the phenotypic and biochemical features in 82 GHIS patients from 23 countries, each fulfilling diagnostic criteria of GHIS. There were 45 males and 37 females [mean age, 8.25 yr; mean height, −6.09 sd score, and mean insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3),− 7.99 sd score]. Sixty-three were GH-binding protein (GHBP) negative; 19 were GHBP positive (>10% binding). The mean height in GHBP-negative subjects was −6.5 sd score, and that in GHBP-positive patients was −4.9 sd score (P = <0.001). Clinical and biochemical heterogeneity was demonstrated by the wide range of height (−2.2 to− 10.4 sd score) and IGFBP-3 (−1.4 to −14.7 sd score) values, which were positively correlated (r2 = 0.45; P = <0.001). This contrasted with the lack of correlation between mean parental height sd score and height sd score (r2 = 0.01). Fifteen different GH receptor gene mutations were identified in 27 patients. All had homozygous defects, except 1 who had a compound heterozygous defect. The mutations were 5 nonsense, 2 frame shift, 4 splice, 4 missense, and 1 compound heterozygote. There was no relationship between mutation type or exon of the GHR gene involved and height or IGFBP-3 sd score. In conclusion, GHIS is associated with wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene. Other genetic and/or environmental factors must, therefore, contribute to phenotype in GHIS.

scholarly journals Growth Hormone (GH) Insensitivity and Insulin-Like Growth Factor-I Deficiency in Inuit Subjects and an Ecuadorian Cohort: Functional Studies of Two Codon 180 GH Receptor Gene Mutations

2008 ◽  
Vol 93 (3) ◽  
pp. 1030-1037 ◽  
Author(s):  
Peng Fang ◽  
Rose Girgis ◽  
Brian M. Little ◽  
Katherine L. Pratt ◽  
Jaime Guevara-Aguirre ◽  
...  
Keyword(s):  
Binding Protein ◽  
Receptor Gene ◽  
Gene Mutations ◽  
Amino Acid Residues ◽  
Dimerization Domain ◽  
Gh Treatment ◽  
Functional Studies ◽  
Gh Receptor ◽  
Igf Binding

Abstract Context: Among more than 250 cases of GH insensitivity syndrome (GHIS) reported to date, the largest cohort was identified in southern Ecuador. In the Ecuadorian GHIS cohort, a sense mutation (GAA > GAG) at codon E180 of GH receptor [GHR (E180sp)] results in deletion of codons 181–188. No functional studies of this mutation have been performed, nor have different mutations at codon 180 been reported. Objective: We now report identification of a novel GHR mutation, also within codon E180, in two distantly related GHIS subjects of Inuit origin and provide mechanistic insights into the defects caused by the Inuit and Ecuadorian GHR mutations. Patients: The two Inuit subjects, with heights of −5 sd score and −7 sd score, respectively, had elevated circulating levels of GH but low levels of GH-binding protein, IGF-I, and IGF-binding protein-3. Results: Both Inuit subjects carry the same novel nonsense homozygous GHR mutation at codon E180 (GAA->TAA, E180X). In vitro reconstitution experiments demonstrated that GHR (E180sp), but not GHR (E180X), could be stably expressed. GHR (E180sp), however, could not bind GH and could neither activate signal transducer and activator of transcription-5b nor induce -5b-dependent gene expression on GH treatment. Furthermore, the GHR (E180sp), which has a deletion of eight amino acid residues within the GHR dimerization domain, although retaining the ability to homodimerize, was defective in trafficking to the cell surface. Conclusions: The E180X mutation identified in two Inuit patients resulted in a truncated, unstably expressed GHR variant, whereas the E180 splicing mutation previously identified in the Ecuadorian cohort, affected both GH binding and GHR trafficking and rendered the abnormal GHR nonfunctional.

scholarly journals The Role of GH in Adipose Tissue: Lessons from Adipose-Specific GH Receptor Gene-Disrupted Mice

2013 ◽  
Vol 27 (3) ◽  
pp. 524-535 ◽  
Author(s):  
Edward O. List ◽  
Darlene E. Berryman ◽  
Kevin Funk ◽  
Elahu S. Gosney ◽  
Adam Jara ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Receptor Gene ◽  
Igf Binding Proteins ◽  
Gh Receptor ◽  
Ghr Gene ◽  
Total Body Fat ◽  
Igf Binding ◽  
Total Body

Abstract GH receptor (GHR) gene-disrupted mice (GHR−/−) have provided countless discoveries as to the numerous actions of GH. Many of these discoveries highlight the importance of GH in adipose tissue. For example GHR−/− mice are insulin sensitive yet obese with preferential enlargement of the sc adipose depot. GHR−/− mice also have elevated levels of leptin, resistin, and adiponectin, compared with controls leading some to suggest that GH may negatively regulate certain adipokines. To help clarify the role that GH exerts specifically on adipose tissue in vivo, we selectively disrupted GHR in adipose tissue to produce Fat GHRKnockout (FaGHRKO) mice. Surprisingly, FaGHRKOs shared only a few characteristics with global GHR−/− mice. Like the GHR−/− mice, FaGHRKO mice are obese with increased total body fat and increased adipocyte size. However, FaGHRKO mice have increases in all adipose depots with no improvements in measures of glucose homeostasis. Furthermore, resistin and adiponectin levels in FaGHRKO mice are similar to controls (or slightly decreased) unlike the increased levels found in GHR−/− mice, suggesting that GH does not regulate these adipokines directly in adipose tissue in vivo. Other features of FaGHRKO mice include decreased levels of adipsin, a near-normal GH/IGF-1 axis, and minimal changes to a large assortment of circulating factors that were measured such as IGF-binding proteins. In conclusion, specific removal of GHR in adipose tissue is sufficient to increase adipose tissue and decrease circulating adipsin. However, removal of GHR in adipose tissue alone is not sufficient to increase levels of resistin or adiponectin and does not alter glucose metabolism.

Specimen processing time and measurement of total insulin-like growth factor-I (IGF-I), free IGF-I, and IGF binding protein-3 (IGFBP-3)

2006 ◽  
Vol 16 (2) ◽  
pp. 86-92 ◽  
Author(s):  
Tiffany G. Harris ◽  
Howard D. Strickler ◽  
Herbert Yu ◽  
Michael N. Pollak ◽  
E. Scott Monrad ◽  
...  
Keyword(s):  
Growth Factor ◽  
Processing Time ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Specimen Processing ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Igfbp 3

scholarly journals Dexamethasone administration attenuates the inhibitory effect of lipopolysaccharide on IGF-I and IGF-binding protein-3 in adult rats

2005 ◽  
Vol 185 (3) ◽  
pp. 467-476 ◽  
Author(s):  
Teresa Priego ◽  
Miriam Granado ◽  
Ana Isabel Martín ◽  
Asunción López-Calderón ◽  
María Angeles Villanúa
Keyword(s):  
Gene Expression ◽  
Inhibitory Effect ◽  
Mrna Levels ◽  
Serum Concentrations ◽  
Gh Receptor ◽  
Its Gene ◽  
Igf I ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Igfbp 3

The aim of this study was to investigate whether glucocorticoid administration had a beneficial effect on serum concentrations of insulin-like growth factor I (IGF-I) and on IGF-binding protein 3 (IGFBP-3) in rats injected with lipopolysaccharide (LPS). Adult male rats were injected with LPS or saline and pretreated with dexamethasone or saline. Dexamethasone administration decreased growth hormone (GH) receptor and IGF-I mRNA levels in the liver of control rats. LPS decreased GH receptor and IGF-I gene expression in the liver of saline-treated rats but not in the liver of dexamethasone-pretreated rats. In the kidney, GH receptor mRNA levels were not modified by dexamethasone or LPS treatment. However, LPS decreased renal IGF-I gene expression and dexamethasone pretreatment prevented this decrease. Serum concentrations of IGF-I were decreased by LPS, and dexamethasone pretreatment attenuated this effect. The gene expression of IGFBP-3 in the liver and kidney and its circulating levels were decreased by LPS. In control rats dexamethasone increased circulating IGFBP-3 and its gene expression in the liver, and decreased the proteolysis of this protein. Dexamethasone pretreatment attenuated the LPS-induced decrease in IGFBP-3 gene expression in the liver and prevented the LPS-induced decrease in IGFBP-3 gene expression in the kidney. Moreover, dexamethasone pretreatment attenuated the LPS-induced decrease in serum concentrations of IGFBP-3 and decreased the LPS-induced IGFBP-3 proteolysis in serum. In conclusion, dexamethasone pretreatment partially attenuates the inhibitory effect of LPS on serum IGF-I by blocking the decrease of its gene expression in the kidney as well as by attenuating the decrease in serum concentrations of IGFBP-3.

scholarly journals Genetic Determinants of Circulating Insulin-Like Growth Factor (IGF)-I, IGF Binding Protein (BP)-1, and IGFBP-3 Levels in a Multiethnic Population

2007 ◽  
Vol 92 (9) ◽  
pp. 3660-3666 ◽  
Author(s):  
Iona Cheng ◽  
Katherine DeLellis Henderson ◽  
Christopher A. Haiman ◽  
Laurence N. Kolonel ◽  
Brian E. Henderson ◽  
...  
Keyword(s):  
Growth Factor ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Genetic Determinants ◽  
Igf I ◽  
Igf Binding ◽  
Multiethnic Population ◽  
Igf Binding Protein ◽  
Igfbp 3

scholarly journals Changes in Plasma Insulin-like Growth Factor (IGF)-1, IGF Binding Protein (IGFBP)-2 and IGFBP-3 during Fasting in Holstein Adult Steers and Calves

2000 ◽  
Vol 71 (2) ◽  
pp. 178-188
Author(s):  
Hong-Gu LEE ◽  
Renato Santa Ana VEGA ◽  
Long Thang PHUNG ◽  
Nobuyoshi MATSUNAGA ◽  
Hideto KUWAYAMA ◽  
...  
Keyword(s):  
Growth Factor ◽  
Plasma Insulin ◽  
Binding Protein ◽  
Insulin Like Growth Factor ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Igfbp 3

scholarly journals Interaction Between IGF Binding Protein-3 and TGFβ in the Regulation of Adipocyte Differentiation

Endocrinology ◽  
2012 ◽  
Vol 153 (10) ◽  
pp. 4799-4807 ◽  
Author(s):  
Hasanthi C. de Silva ◽  
Sue M. Firth ◽  
Stephen M. Twigg ◽  
Robert C. Baxter
Keyword(s):  
Binding Protein ◽  
Adipogenic Differentiation ◽  
Cell Types ◽  
Inhibitory Effect ◽  
Down Regulation ◽  
Smad2 Phosphorylation ◽  
Igf Binding ◽  
Igf Binding Protein ◽  
Interfering Rna ◽  
Igfbp 3

Abstract The development of white adipose tissue involves both the hypertrophy of existing adipocytes and the proliferation and differentiation of preadipocytes. Adipogenic differentiation is inhibited by TGFβ signaling through Smad2/3, and IGF binding protein-3 (IGFBP-3) is also known to activate Smad2/3 signaling in some cell types. We previously reported that exogenous or overexpressed IGFBP-3 inhibits adipogenesis in 3T3-L1 cells, but the role of endogenous IGFBP-3 in this process, and its possible interaction with TGFβ, is not known. During 10-d adipogenic differentiation initiated by insulin, dexamethasone, and 3-isobutyl-1-methylxanthine, 3T3-L1 cells expressed increasing levels of IGFBP-3 and TGFβ1, secreting over 1000 pg/ml of both proteins. Exogenous recombinant human IGFBP-3 paralleled TGFβ1 in stimulating Smad2 phosphorylation in 3T3-L1 preadipocytes, but no additive effect was observed for the two agents. In contrast, knockdown of endogenous IGFBP-3 by small interfering RNA (siRNA) significantly impaired Smad2 activation by 0.25 ng/ml TGFβ1. Transient expression of human IGFBP-3 significantly inhibited the induction of adipogenic markers adiponectin and resistin, and the appearance of lipid droplets, but down-regulation of endogenous IGFBP-3 by siRNA had little effect on the expression of either marker during the 10-d differentiation, compared with nonsilencing control siRNA. However, down-regulation of endogenous IGFBP-3 using two different siRNA significantly reversed the inhibitory effect of TGFβ1 on both adiponectin and resistin induction. We conclude that IGFBP-3 activates inhibitory Smad signaling in 3T3-L1 cells and that endogenous IGFBP-3 modulates their adipogenic differentiation by regulating cell sensitivity towards the inhibitory effect of TGFβ.

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